Chronic methamphetamine abuse in human subjects is associated with neuronal toxicity, expressed behaviorally as cognitive deficits. Positron emission tomography (PET) and [F-18]fluorodeoxyglucose were used to determine the effects of methamphetamine self-administration on basal cerebral metabolism in four drug-naive Rhesus monkeys (3-5 y.o.). Prior to the baseline PET study, the subjects were trained to respond for food on a fixed ratio (FR) 30 schedule. The monkeys were then trained to self-administer methamphetamine (0.025 mg/kg/injection) on an FR 10 schedule. A second PET FDG scan was acquired at the end of the methamphetamine training period, which lasted 30-82 days during which the monkeys received a total of 40.9 - 104.9 mg/kg of methamphetamine. At the time of the second PET scan, the monkeys had not self-administered methamphetamine for at least 24 h. The images from the PET studies were normalized by dividing the regional values by global counts. Using an ROI template with 28 regions on co-registered images, we found significantly increased metabolism after methamphetamine administration in right and left frontal cortices and left thalamus. Our results suggest that the higher normalized rates of glucose metabolism observed in cortical areas of human methamphetamine abusers could be a consequence of their history of drug abuse rather than due to predrug trait differences. Studies in rats were initiated to establish a model in which the time course to toxicity, reversibility of effects and potential effects of treatment modalities could be tested. Rats were subjected to a chronic treatment regimen that was designed to mimic the manner in which human methamphetamine abusers self-administer the drug. The effects of brain function were assessed using the 2-deoxy-D-[1-[C-14]]glucose (DG) method, which provides quantitative maps of regional cerebral metabolic rates for glucose (rCMRglc), an index of brain function. Compared to effects in control animals, chronic methamphetamine produced lower rCMRglc in 14 out of 34 regions assayed and in whole brain. The most robust effects occurred in the retrosplenial cortex, head of the caudate putamen, ventroposterior thalamic n. and core of the nucleus accumbens. Lower basal brain metabolism in rats receiving chronic methamphetamine may reflect the toxic effects of chronic use of this drug. The wide distribution of the metabolic effects of methamphetamine in the rat brain suggests that human abusers of this drug have extensive cerebral deficits that underlie their cognitive and emotional symptoms.